Classic Phenylketonuria · PKU

Description

Classic phenylketonuria, PKU, is an inherited inability to break down the amino acid phenylalanine. The enzyme phenylalanine hydroxylase, encoded by the PAH gene, converts phenylalanine to tyrosine. Two damaging copies of PAH leave the enzyme partially or fully nonfunctional, phenylalanine accumulates in blood and brain, and untreated children develop severe intellectual disability, seizures, and behavioral disturbances by the second year of life. Inheritance is autosomal recessive. Incidence in the United States is roughly 1 in 10,000 to 1 in 25,000 newborns.

Worldwide incidence of PKU varies sharply by country. Pooled neonatal-screening data place the global rate at about 1 in 17,000 births. Türkiye reports the highest national prevalence at roughly 1 in 4,000, an excess attributed to high rates of consanguineous marriage. Universal newborn screening is uncommon across most of sub-Saharan Africa, where children with PKU are typically identified only after symptoms appear.

Detection is by newborn screening on the dried blood spot, using tandem mass spectrometry. Confirmation uses quantitative plasma amino acids and PAH gene sequencing. A separate workup rules out defects in tetrahydrobiopterin (BH4) synthesis or recycling, which raise blood phenylalanine through a different mechanism and need a different treatment. Treatment is initiated when sustained blood phenylalanine exceeds 360 µmol/L (6 mg/dL), and US guidelines call for lifelong control within roughly 120 to 360 µmol/L. A subset of people with PKU carry residual enzyme activity that responds to BH4 cofactor.

Maternal PKU is a related condition with separate management. A pregnant woman with PKU must maintain blood phenylalanine control before conception and through pregnancy. Without that control the fetus is exposed to high phenylalanine, and the documented consequences are congenital heart defects, microcephaly, and intellectual disability. Strict pre-conception control changes the fetal outcome.

Treatments to date

Lifelong dietary control of phenylalanine has been the standard of care since the early 1950s. Treatment is started in the first weeks of life after a positive screen and continued through adulthood. The diet restricts natural protein, replaces the missing protein intake with phenylalanine-free medical formula, and uses modified low-protein staple foods to maintain calorie and nutrient targets.

Sapropterin dihydrochloride was approved by the FDA in December 2007 as the first specific drug therapy for PKU. It is a synthetic form of the BH4 cofactor and reduces blood phenylalanine in the responsive subset, defined by residual enzyme activity. Sapropterin is taken orally with the diet, and a generic version became available in 2018.

Pegvaliase, an injectable enzyme substitution therapy that degrades phenylalanine in the bloodstream, was approved by the FDA in May 2018 for adults with uncontrolled blood phenylalanine, and approval was extended to adolescents 12 and older in February 2026. Pegvaliase is delivered under a Risk Evaluation and Mitigation Strategy because anaphylaxis occurs in a meaningful minority of recipients.

Sepiapterin was approved by the FDA in July 2025 for hyperphenylalaninemia in sepiapterin-responsive PKU at any age from one month and older. It is a natural precursor of BH4 and is taken orally with the diet.

In vivo gene editing for PKU is in development. The Beam Therapeutics PAH base-editing program advanced in 2026 with an Investigational New Drug filing anticipated that year and a planned Phase 1/2 dose exploration. Other approaches in development include AAV-delivered PAH replacement and engineered gut bacteria designed to degrade phenylalanine.